In the US, heart disease remains the most common cause of death. Because a large volume of functional muscle is replaced by fibrotic scar following a large myocardial infarction, there has been tremendous interest in strategies to regenerate the diseased myocardium. Cell therapy is appealing to provide cells that will ideally regenerate the damaged heart; however, the results of clinical trials to date have not shown clear benefit in most cases from cell therapy. The lack of robust clinical benefit could be due to multiple factors, but particularly we suggest that the optimal cell preparations have not been tested. The cell populations with the most robust capacity to form new cardiac muscle are cardiac progenitors present during heart development. Therefore, our central hypothesis is that distinct populations of cardiac progenitor cells can be isolated from the native heart or pluripotent stem cells as well as by direct reprogramming of somatic cells that will exhibit superior ability to repair the injured myocardium compared to differentiated cell types. However, we have incomplete understanding of the distinct cardiac progenitor populations responsible for the developing heart, and our ability to isolate these cardiac progenitors is limited. We propose to address these limitations in three aims: 1) identify and isolate first heart field, left ventriclar progenitor cells from developing mouse heart and mESCs; 2) test transplantation of CPCs and direct in vivo reprogramming to iCPCs in cardiac repair post-MI; and 3) generate proliferative, multipotent human induced CPCs. This research will advance our understanding of cardiac progenitors, provide new tools for the isolation and study of CPCs, and test powerful new approaches for post-MI cardiac repair.